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A review of ruthenium complexes activities on different steps of the metastatic

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Popolin, C.P. and Cominetti, M.R. Mini-Reviews in Medicinal Chemistry, 2017, Vol. 0, No. 0 1

A review of ruthenium complexes activities on breast cancer cells

Cecília P. Popolina and Márcia R. Cominettia*
a
Departamento de Gerontologia, Universidade Federal de São Carlos. Rod. Washington Luis, Km 235, São Carlos, SP,
13565-905.

Abstract: Cancer is one of the main causes of death worldwide. Breast cancer is the most prevalent type of cancer in
women and the leading cause of cancer deaths due to its high metastasis to the lymph nodes, lungs bones and brain.
Interactions with the stromal microenvironment surrounding tumor cells facilitate tumor cell migration and invasion of
tissues and dissemination to other organs, to form metastasis. The development of antitumor metal-based drugs was
originated with the discovery of cisplatin, however, its severe side effects represent a limitation for its clinical use.
Ruthenium complexes (Ru) with different ligands have been successfully studied as promising antitumor drugs. In this
review, we focused on the effects of Ru complexes on breast cancer cells and its impact on different steps of the
metastatic process.
Keywords: Ruthenium complexes, breast cancer, metastasis, proliferation, migration, apoptosis.

1. INTRODUCTION Using the bloodstream to spread throughout the body, cancer

Breast cancer is the second most common cancer in the
world and the most prevalent type of cancer in women. Over
the last few years, metastatic breast cancer has been one of
the leading causes of death in women due to the metastasis
formation in lymph nodes, lungs, bones and brain [1].
Metastasis is an exceedingly complex process, which
occurs through a series of sequential steps that include the
invasion of adjacent tissues, intravasation, transport through
the circulatory system, arrest at a secondary site,
extravasation and growth in a secondary organ. Metastases
are the cause of 90% of human cancer deaths [2]. A small
proportion of cancer cells from a primary tumor acquire
invasive and migratory properties. The acquisition of
invasive behavior is one of the first steps in the metastatic
process and it is driven by cycles of actin polymerization,
cell adhesion and acto-myosin contraction. There are
different modes of motility and some tumor cells can switch
between them. Such plasticity can enable tumor cells to
continue moving even when one type of motility has been
prevented by pharmacological means [3].
Cells that leave a primary tumor invade their surrounding
tissues using one of several types of invasion, and some of
the cells will migrate towards the neighboring blood vessels.
Cancer cells enter the bloodstream in a process called
intravasation, in which cells migrate through endothelial cell
(EC) junctions. It has been described that tumor areas with
numerous moving breast cancer cells also have high numbers
of tumor-associated macrophages (TAM) [4]. TAM can
promote the invasive behavior of the cancer cells by
producing epidermal growth factor (EGF) [5] and often
cluster around blood vessels and the tumor margin,
establishing EGF gradients within the tumor environment
that attract tumor cells towards vessels and thereby promote
intravasation [4].
*Address correspondence to this author at Departamento de
Gerontologia, Universidade Federal de São Carlos. Rod.
Washington Luis, Km 235, São Carlos, SP, 13565-905, Phone:
+55 16 3306 6663. E-mail: mcominetti@ufscar.br
cells then leave the circulation in a process called
extravasation at potential secondary tumor sites. It is likely
that many of the same molecular functions required for cell
motility in the primary tumor will be required for
extravasation [3]. Cancer cells then transmigrate through the
endothelial barrier in a process called transendothelial
migration (TEM), and afterwards invade the basement
membrane that surrounds the blood vessels. Cells can next
undergo apoptosis within 24 hours, be cleared by immune
cells [3], enter a state of dormancy or proliferate within this
new microenvironment, where a few of them will give rise to
micrometastases and then macrometastases [6, 7].
Treatment of breast cancer has as main objectives to
increase survival and improve the quality of life. Surgery and
radiotherapy are treatments used for local control of breast
cancer; on the other hand, systemic treatment is made by
hormone therapy and chemotherapy [8-10]. Drugs used in
chemotherapy cause resistance and damage to DNA, not
only from tumor, but also from normal cells.
Rosenberg and colleagues in 1964 were responsible for
the discovery of cisplatin, that posteriorly proved to be an
effective complex for the treatment of different cancer types,
including breast [11]. Despite the success of platinum-based
drugs, their continued use is greatly limited by severe dose
limiting side effects and intrinsic or acquired drug resistance
[12]. With the limitations of cisplatin, new research has been
developed with low toxicity compounds, such as ruthenium
(Ru) complexes.
There are some hypotheses to explain the low toxicity
and the antitumor and antimetastatic properties of Ru
compounds. Ru seems to accumulate preferentially in the
tumors rather than in normal tissues, possibly by using
transferrin receptors [13], since they are able to mimic the
binding of iron to these receptors [14]. It has been proposed
that tumors contain high amounts of transferrin receptors,
allowing Ru complexes to be actively transported into
neoplastic tissues that require higher iron requirement [15].
Once bound to the transferrin receptor, Ru would be
Popolin, C.P. and Cominetti, M.R.
internalized by the tumor [16]. In addition, Ru complexes
could be considered pro-drugs. Ru remains in its relatively
inactive Ru(III) oxidation state until it reaches the tumor site.
Tumors have a lower oxygen content and higher acidity
compared to normal tissues and reduction to the more
reactive Ru(II) occurs [17]. This reaction causes selective
tumor targeting by direct cytotoxic activity toward hypoxic
tumors [18]. In addition, due to their slow ligand exchange
kinetics, in the range of minutes to days, instead of
microseconds to seconds, they present general inertness,
preventing rapid equilibration reactions [19]. Moreover, Ru
complexes have unique DNA binding patterns due to their
special octahedral structure and ligand geometries [20].
These would allow them to inhibit DNA replication, to have
mutagenic activity, induce SOS repair, bind to nuclear DNA
and reduce of RNA synthesis, which are all consistent with
their reported effects [14]. Finally, their photoactivated
biological applications make these complexes still more
attractive. Photocaged Ru complexes are usually nontoxic to
non-irradiated tissues and can become toxic in tumor cells
through photoactivation [21].
Currently, one Ru complex, NKP-1339 (sodium trans-
[tetrachloridobis(1H-indazole)ruthenate(III), is ongoing
clinical trials. NKP-1339 has entered clinical trials as the
more soluble alternative to the indazolium compound
KP1019 [22] and shows promising results in solid tumors,
such as non-small cell lung cancer, colorectal carcinoma, and
most distinctively in gastrointestinal neuroendocrine tumors
[23].
The aim of this review is to summarize the most recent in
vitro and in vivo studies on action of Ru complexes on the
breast cancer. We will focus on specific steps of the
metastatic process, including cell adhesion, migration,
invasion and describe the effects on each of these steps. In
particular we will discuss the antitumor effects of Ru
complexes and their ability to inhibit the above cited
processes and to induce apoptosis. This review is divided
into two parts describing first results from in vitro studies
and then those performed in different animal models in vivo.
It was prepared using publications reported on the NLM-
Pubmed online bibliographic database, using the keywords
“ruthenium” and “breast cancer”, totaling 109 papers.
Excluding works using other compounds or cell lines, a total
of 27 articles were consulted for this review.
IN VITRO ANTITUMOR EFFECTS
OF RUTHENIUM COMPLEXES ON BREAST
CANCER CELLS
Our search of the literature identified the anti-
proliferative, anti-adhesive, anti-migratory, anti-invasive and
pro-apoptotic effects of several Ru complexes on breast
cancer cells. The in vitro and in vivo effects in breast cancer
models are summarized in Table 1. The vast majority of the
complexes inhibits breast tumor cell proliferation ranging
from nano to micromolar IC50 concentrations. However, to
the best of our knowledge, only one study described the
effects on both breast tumor and non-tumor cell lines. Ru
complex with -phenylenediamine as the N-N ligand (-
PDA) significantly inhibited growth of breast cell lines
MDA-MB-231 and MCF-7, but was ineffective to inhibit
Mini-Reviews in Medicinal Chemistry, 2017, Vol. 0, No. 0 2
growth of human non-tumor breast epithelial cells, MCF-
10A [24]. This selective cytotoxicity against tumor cells
could be explained, at least in part, by the Ru ability to be
internalized preferentially by tumor cells, as described
earlier.
Wu et al. [25] have demonstrated the effect of arene
ruthenium(II) complex (RAWQ11) against migration and
invasion of MDA-MB-231 cells. The inhibitory effect of
RAWQ11 against migration of MDA-MB-231 cells was
evaluated by wound healing assay. Compared to control cells
that spontaneously migrated, treatment of MDA-MB-231
cells with RAWQ11 showed a small decrease in the time of
wound closure at 48h, in a concentration-dependent manner.
The invasion of MDA-MB-231 cells was also blocked in a
concentration-dependent manner starting from 1µM. Authors
demonstrated by western blotting analysis that RAWQ11
reduce cell invasion and migration, at least in part, due to the
inhibition of proMMP-9 secretion and increased GSK3, a
negative regulator of MMP [25].
In another study it was demonstrated that Ru polypyridyl
complex (RuPOP) inhibits MDA-MB-231 cell migration and
invasion at concentrations ranging from 1 to 4µM after 24h
treatment, through downregulation of MMP-9 expression
and upregulation of TIMP-1 (a tissue inhibitor of
metalloproteinases) [26]. Similar results were found for cell
migration in MDA-MB-231 and MCF-7 cells with an
organometallic Ru complex (RAPTA-T) [27].
Cell adhesion plays a critical role in regulating tumor cell
migration and invasion during metastasis [28]. Mazuryk et
al. [29] investigated the influence of [Ru(dip)2(bpy-
NitroIm)]2+ and [Ru(dip)2(bpy)]2+ on adhesion of a murine
triple negative cell line (4T1) and the ability of treated cells
to attach to different types of extracellular matrix (ECM)
coating, using different proteins such as fibronectin, collagen
and plastic. Treatments with both Ru complexes resulted in
significant decrease of cell adhesion to ECM proteins at
concentrations 1.5 and 3µM. Cell adhesion effects were
more effective for [Ru(dip)2(bpy)]2+[29].
Apoptosis or programmed cell death is a basic cellular
process critical to the maintenance of tissue homeostasis
[30]. Apoptosis is carried out by two major pathways, the
receptor (extrinsic) pathway and the mitochondrial (intrinsic)
pathway, which eventually result in the activation of
caspases, a family of enzymes that act as effector molecules
in various forms of cell death [31]. Evasion of apoptosis is
one of the hallmarks of cancer and represents an important
mechanism in clinical resistance to therapies [32, 33].
Frequently, chemotherapy drives tumor cells to develop
resistance to cytotoxic agents and radiation, consequently
leading to resistance to apoptosis and in inefficiency in
cancer treatment [34]. Ru complexes that arrest cell cycle
and/or (re)induce apoptosis in tumor cells could be a
promising strategy for breast cancer treatment.
Nhukeaw and colleagues [35] evaluated the effects of
metallo-intercalator ruthenium(II) complexes with the
Clazpy ligand, [Ru(Clazpy)2bpy]Cl2.7H2O and
[Ru(Clazpy)2phen]Cl2.8H2O in the induction of apoptosis in
three breast tumor cell lines (MDA-MB-231, MCF-7 and
Popolin, C.P. and Cominetti, M.R. Mini-Reviews in Medicinal Chemistry, 2017, Vol. 0, No. 0 3

Table 1. Effects in vitro and in vivo of ruthenium complexes on different breast cancer cell lines.
Symbols (+) or (-) represent induction or inhibition of the process, respectively. 1 Represents co-treatment with TRAIL (2 and 4ng/ml).

In vitro
Ruthenium complexes Cell line Concentration (µM±SD) Effect Reference
Adhesion
[Ru(dip)2(bpy-NitroIm)]2+ 4T1 1.5 and 3 - [29]
[Ru(dip)2(bpy)]2+ 4T1 1.5 and 3 - [29]
Migration
RAWQ11 MDA-MB-231 1 and 2 - [25]
RuPOP MDA-MB-231 1 to 4 - [26]
RAPTA-T MDA-MB-231 100 - [27]
RAPTA-T MCF-7 100 - [27]
Invasion
RAWQ11 MDA-MB-231 1 to 20 - [25]
RuPOP MDA-MB-231 1 to 4 - [26]
RAPTA-T MDA-MB-231 100 - [27]
RAPTA-T MCF-7 100 - [27]
Apoptosis
[Ru(Clazpy)2bpy]Cl2.7H2O MDA-MB-231 14.1±0.5 + [35]
[Ru(Clazpy)2bpy]Cl2.7H2O MCF-7 10.7±0.6 + [35]
[Ru(Clazpy)2bpy]Cl2.7H2O HCC1932 9.9±0.2 + [35]
[Ru(Clazpy)2phen]Cl2.8H2O MDA-MB-231 13.2±0.3 + [35]
[Ru(dip)2-(bpy)]2+ 4T1 2 and 4 + [29]
[Ru(dip)2(bpy-NitroIm)]2+ 4T1 2 and 4 + [29]
ethaRAPTA MCF-7 20 + [36]
RuPOP+TRAIL MDA-MB-231 2¹ + [26]
DiRu-1 MCF-7 0.038 to 0.154 + [37]
Λ-RM0627 MDA-MB-231 40 - [38]
In vivo
Ruthenium complexes Animal Dose (mg/Kg/day) Effect Reference
[(η6-p-Cymene)Ru{(Ph3P=N-CO-2-N- NOD.CB17-Prkdc scid/J mice 14 (5) - [39]
C5H4)-κ-N,O}Cl]Cl
UNICAM-1 FVB/NCrl mice 4 (52.5) - [40]
RAPTA-T CBA mice 3 (80) - [27]
RM175 CBA mice 6 (10) - [41]
G26b BALB/c mice 6 (17.5) - [42]
ruthenium(II)-cyclopentadienyl N:NIH(S)II-nu/nu nude mice 10 (2.5) - [43]
HCC1932). A significant increase in MDA-MB-231 (1,3,5-triaza-7-phosphaadamantane) dichloride, termed
apoptotic cells was observed, with slightly less apoptotic ethaRAPTA gives rise to a significant increase in the
rates in HCC1937 and MCF-7 cells, respectively. The apoptotic population on MCF-7 cells, with the lower right
authors showed that significant increase in apoptotic cells in count increasing four fold over a 24h period and six fold
the triple negative MDA-MB-231 cells could result from the over 48h, with a correlated decrease in the lower left count
over-expression of the epidermal growth factor (EGF)- [36].
induced nuclear factor NF-κB that controls the cell-cycle
Apoptosis was detected in MDA-MB-231 cells after
progression [35].
incubation with Ru polypyridyl complex (RuPOP) and
Mazuryk et al. [29] investigated the influence of Ru TRAIL (tumor necrosis factor-related apoptosis-inducing
polypyridyl complexes [Ru(dip)2(bpy-NitroIm)]2+ and ligand). Results showed that exposure of MDA-MB-231
[Ru(dip)2-(bpy)]2+ on cell cycle progression in 4T1 cell line cells to RuPOP and/or TRAIL resulted in an increase in the
determined by flow cytometry using staining with propidium number of apoptotic cells. Caspases are important class of
iodide. Results showed that after a 24h treatment Ru cysteine acid proteases that play roles in control of apoptosis
complexes caused a reduction in the G0/G1 phase by activation of various cellular substrates. Results revealed
accompanied by a corresponding increase in the percentage a remarkably increase in caspase-3 activity induced by the
of cells in the S phase. These data suggest that the co-treatment of the RuPOP and TRAIL. To further confirm
antiproliferative mechanism of tested Ru polypyridyl these data, western blot analysis was used to determine the
complexes is based on S-phase arrest. caspase activation and PARP cleavage, a biomarker of
apoptosis. Co-treatment with RuPOP and TRAIL effectively
Chartterjee and colleagues [36] demonstrated that the
triggered the activation of caspases-3/-8/-9 and cleaved
treatment with an organometallic glutathione S-transferase
PARP in MDA-MB-231 cells. Taken together, the above
inhibitor ruthenium(II) (ethacrynic acid-g6-benzylamide)
evidences suggest that RuPOP potentiated TRAIL-induced
apoptosis though intrinsic and extrinsic apoptotic pathways
in breast tumor cells [26].
Popolin, C.P. and Cominetti, M.R.
The activity of the dinuclear trithiolato-bridged arene Ru
complex diruthenium-1 (DiRu-1) was demonstrated to be
cytotoxic against MCF-7 and MDA-MB-231 cells. MCF-7
cells were more responsive to the effects of DiRu-1, possibly
due to its ability to induce oxidative stress, apoptosis, and
DNA damage, and to inhibit the cell cycle and proliferation.
DiRu-1 triggers caspase-dependent apoptosis in this cell line
on both the intrinsic and extrinsic pathways. Moreover, the
Ru complex also caused necrosis, mitotic catastrophe, and
autophagy. DiRu-1 increases the intracellular levels of
reactive oxygen species (ROS), which play a significant role
in its cytotoxicity and pro-apoptotic activity. DiRu-1 appears
to be the induce DNA lesions, mainly due to apoptotic DNA
fragmentation and cell-cycle arrest at the G2 /M checkpoint
in a concentration and time-dependent manner [37].
In contrast, Zeng and coworkers [38] found that 40µM of
Ru complex Λ-RM0627 exhibited little apoptosis inducing
effect on MDA-MB-231 cells, with only 6.2% cells in the
late stage and 21.8% cells in the early stage of apoptosis;
thus, about 70% of the cells were not affected by Λ-RM0627
treatment [38].
Structure-activity relationships of Ru complexes on
breast tumor cells have been demonstrated. Several
properties of Ru complexes influence their activities, such as
the size and the lipophilicity of the complex and the type of
ligand. In this sense, Ru has been used as a scaffold to
organize several well-established bioactive organic
pharmacophores around the metal center [44, 45] allowing a
myriad of different combinations. It is not the focus of this
review, but to give few examples, the photophysical
properties of five ruthenium(II) complexes comprising two
4,7-diphenyl-1,10-phenanthroline (dip) ligands and
functionalized bipyridine (R1bpy-R2, where R1 = H or CH3,
R2 = H, CH3, COO-,4-[3-(2-nitro-1H-imidazol-1-yl)propyl]
or 1,3-dicyclohexyl-1-carbonyl-urea) were demonstrated and
it was shown that the lipophilicity and complex charge
determine the level of their intracellular uptake in 4T1 cells,
which explains their cytotoxicity and imaging properties.
The monocationic [Ru(dip)2(CH3bpy-COO)]+ complex has
much smaller accumulation compared to the other studied
complexes, despite having the highest logP value, whereas
the rise of the accumulation for dicationic complexes
correlates with their increased lipophilicity [46]. Regarding
cytotoxicity, among the tested compounds
[Ru(dip)2(CH3bpy-DCU)]2+ and [Ru(dip)2(CH3bpyCH3)]2+
were the most toxic for 4T1 cells. One explanation for this
effect is the higher lipophilicity of the former and smaller
size of the later one, which should facilitate their uptake.
[Ru(dip)2(CH3bpy-COO)]+ was less toxic for 4T1 cells
despite the highest lipophilicity, this may be due to its lower
accumulation as confirmed by uptake studies [46].
The Ru ligands were found to play a critical role in their
activities. [(g6-arene)Ru(ethylenediamine)Cl]+ complexes
display significant selectivity for binding DNA guanine
bases, facilitated by H-bonding between the ethylenediamine
NH2 groups and the exocyclic oxygens of guanine [45].
Finally, in the pseudo octahedral “piano-stool” Ru(II)
Mini-Reviews in Medicinal Chemistry, 2017, Vol. 0, No. 0 4
complexes, a -bonded arene occupies three coordination
sites, and the two nitrogens of ethylenediamine (en) and the
leaving group (e.g., Cl) fill the remaining three sites. The
presence of an arene greatly stabilizes Ru(II) compared to
Ru(III) allowing them to exhibit their biological effects
Taken together, the results above demonstrate the effects
of Ru complexes on the function of multiple breast tumor
cell types. The high variability found among effective
concentrations to act on breast tumor cells can be explained
by the variability in the complexes structure, as well as the
origins and specificities of the cells lines used in the assays.
Nonetheless, inhibition of cell proliferation, adhesion,
migration and invasion and induction of apoptosis indicates
that Ru complexes may have direct anti-tumor and/or anti-
metastatic activities in vivo, which may contribute to the
development of new antitumor drugs to be applied in
chemotherapy.
IN VIVO ANTITUMOR AND ANTIMETASTATIC
EFFECTS OF RUTHENIUM COMPLEXES.
The in vivo effects of an organometallic ruthenium(II)
[(η6-p-Cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl
complex has been demonstrated on xenografted breast
carcinoma MDA-MB-231 tumors grown on NOD.CB17-
Prkdc scid/J mice. An impressive tumor reduction
(shrinkage) of 56% was observed after 28 days treatment (14
doses of 5mg/kg every other day) with low systemic toxicity.
Pharmacokinetic studies showed a rapid absorption of the
complex in plasma with an elimination half-life of 12 hours.
Authors conclude that the complex is a good candidate for
further evaluation as a potential chemotherapeutic agent
[39].
Montani and colleagues [40] investigated the in vivo
antineoplastic effects of the Ru complex [Ru(p-
cymene)(bis(3,5-dimethylpyrazol-1-l)methane)Cl]Cl, termed
UNICAM-1 against triple negative A17 cells, which are able
to give rise to aggressive mesenchymal tumors when injected
into syngeneic mice. Results revealed that A17 tumor cells
grow rate and the final tumor dimensions were significantly
reduced in the animals treated with according to protocol q3
× 4, UNICAM-1 (52.5 mg/kg/day), cisplatin (3 mg/Kg/day)
or NAMI-A (52.5 mg/kg/day), repeated 4 times at 3 days
intervals. However, NAMI-A treatment was less effective in
reducing tumor growth. While all control mice developed
palpable tumors after two weeks after A17 cell challenge,
two of the total ten mice treated with UNICAM-1 did not
develop palpable tumors until the end of the experiment. In
addition, UNICAM-1 treated mice developed very small
tumors, with an average diameter never exceeding 3 mm.
Interestingly, body weight did not significantly differ
between UNICAM-1-treated and control mice, suggesting
the absence of drug toxicity at the selected dose level. On the
contrary, both NAMI-A and cisplatin treatments were
associated with weight loss. Therefore, in this work authors
concluded that UNICAM-1 exhibits a marked anti-tumor
activity in vivo against an experimental TNBC model,
associated with low toxicity [40].
Popolin, C.P. and Cominetti, M.R.
Fig 1. Scheme of the possible biological mechanisms of ruthenium complexes in vivo.
Bergamo and colleagues [27] described that RAPTA-T
[Ru(η6-toluene)Cl2(PTA)] selectively reduces the growth of
lung metastases originated from MCa mammary carcinoma
primary tumor at concentrations of 80mg/kg/day for 3 days.
In the same mammary carcinoma model, RM175 ([(g6-
biphenyl)M(ethylenediamine)Cl]+) complex reduced by
about 95% the size of measurable lung metastasis at
10mg/Kg/day. However, at this daily dose a significant
toxicity was registered in 6 out of 10 mice. Intriguingly,
RM175 showed significant activity against cancer metastases
but had minimal effects on the growing of primary tumor
[41].
Recently, the antimetastatic effects of two novel NAMI-
A derivatives containing pyridine, named G26b and G94a,
were evaluated. The former G26b, at a dose of 17.5mg/kg
per day, significantly reduced the occurrence and
development of lung metastases in mice bearing the 4T1
mammary carcinoma, with no retinal toxicity or
hepatotoxicity [42].
Very recently, Mendes and co-workers [43] reported that
new organometallic ruthenium(II)-cyclopentadienyl
complexes have anti-tumor and anti-metastatic effects in vivo
on N:NIH(S)II-nu/nu nude female mice bearing triple
negative breast cancer orthotopic tumors. Administration of
2.5 mg/kg/day during ten days caused cell death mostly by
necrosis (in vitro and in vivo), inducing tumor growth
suppression of about 50% in treated animals when compared
to controls. The complex not only suppressed the growth of
primary tumor tissue, but also inhibited metastases in the
main organs of treated animals, but not in the lungs of all
control mice [43].
Taken together, in view of these properties, Ru
complexes are predicted to show distinct patterns of
antitumor and antimetastatic activities and clinical toxicity.
The possible biological mechanisms of action are
summarized on Figure 1. In general, in vivo studies in animal
models using Ru complexes showed low toxicity and
therapeutic potential for inhibition of tumor growth and
metastasis in different animal models. However, the
therapeutic failure of NAMI-A and KP-1019 to surpass
clinical trials has concerned researchers in the field. In a
recent study, NAMI-A in combination with gemcitabine,
demonstrated to be only moderately tolerated by patients and
Mini-Reviews in Medicinal Chemistry, 2017, Vol. 0, No. 0 5
less active in non-small cell lung cancer patients after first
line treatment than gemcitabine alone [19]. Although Ru
complexes could be considered as potential candidates for
new antimetastatic drugs showing a variety of mechanisms
of action in pre clinic studies, their future use in
chemotherapy remains uncertain at present, due to their
toxicity profile and the lack of convincing preliminary
efficacy results.
CONCLUSION
It is possible to conclude that Ru complexes act on
different steps of the metastatic process, from tumor cell
adhesion to other processes such as cell migration, invasion,
and proliferation. Furthermore, Ru complexes induce
apoptosis in different breast cancer cell lines. The review
highlighted a number of in vitro and in vivo results indicating
that additional studies should be performed in order to
definitely prove the clinical efficacy of Ru complexes for
cancer chemotherapy.
ACKNOWLEDGEMENTS
The authors are grateful for the financial support of
FAPESP (Fundação de Amparo à Pesquisa do Estado de São
Paulo, grant #2013/00798-2). CPP has a scholarship
sponsored by CNPq (Conselho Nacional de
Desenvolvimento Científico e Tecnológico).
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